Wnt/Notch signalling in developmental homeostasis

Figure 1

The patterning of an organism relies on the coordinated generation of different cell types from an otherwise homogeneous population. This requires a great deal of coordination which is achieved by interactions between extracellular signalling and the transcriptional networks of the cell. Analysis of this relationships in different systems have led us to the observation that two signalling pathways, Notch and Wnt, play a distinct function in development: determining the probability with which a cell adopts a fate.

This view is derived from the observation that a process of cell fate assignation can be decomposed into two steps. One, an initial phase in which cells are given the potential to adopt a fate and two, a stablization phase in which the fate is consolidated in some (but not all) of the cells in which it has been initiated. This underpins the well established fact that cells in development have potentials and fates and that their potentials are bigger than their fates.

Figure 2

At the molecular level it is possible to separate the two steps. This can be clearly seen in the development of the Peripheral Nervous System of Drosophila, where the spatial and temporal regulation of genes of the achaete/scute complex determines the pattern of sensory organ precursors (SOPs). Members of the ac/sc complex become expressed in clusters of cells with defined spatial coordinates from which precursors arise (Fig. 1). Analysis of the regulation of the ac/sc complex has uncovered complex spatial and temporal elements that regulate each cluster separately but then, mutations in elements of the Notch and Wnt signaling pathways affect all clusters in a similar way. Normally only one or two cells in each cluster become SOP, but in the absence of Notch ALL cells in the cluster become SOPs. Conversely in the absence of Wingless (the Drosophila Wnt-1), none of the cells of the cluster becomes an SOP (Fig.2). Neither Notch nor Wnt mutants affect the initiation of the expression in the clusters. This suggests to us that within each cluster cells are measuring the relative levels and strengths of Wnt and Notch signaling to decide whether or not to become an SOP i.e. the relative levels of Wnt and Notch signaling determine the probability with which the cells adopt the fate (Fig.2). Interestingly the precursors arise from the region of the cluster nearer to the source of Wingless. Thus, if Wnt>Notch, SOP fate results.(Fig.2).

On this basis we have suggested that GRNs can create transiently noisy patterns of expression of fate determining genes and that the integrated action of Wnt and Notch signaling tips the balance one way or another. In fact we believe that the outputs of GRNs are always noisy.

Figure 3

Over the years we have been characterizing the interactions between Wnt and Notch in Drosophila and recently we have been looking at the emerging information from other systems, particularly vertebrates. These observations have led us to suggest that the two pathways are integrated into a module that we chose to call Wntch, and which acts as a transistor in cell fate assignments (Fig.3). The transistor has a structure that allows it to filter and amplify signals that the cells receive from other sources, and in development it acts to eliminate the noise from the pattern and to generate the specific functional set of cell fates and patterns correctly.

At the moment we are pursuing the structure and function of the Wntch module in mouse ES cells and the Drosophila midgut using a combination of genetics, quantitative cell biology, and live imaging of fluorescent reporters.